Elbasvir/grazoprevir combines two direct-acting antiviral agents with distinct mechanisms of action and nonoverlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly.
Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant NS3/4A protease enzymes from HCV genotypes 1a, 1b, 3 and 4a with IC50 values ranging from 4 to 690 pM.
The EC50 values of elbasvir and grazoprevir against full-length or chimeric replicons encoding NS5A or NS3 sequences from reference sequences and clinical isolates are presented in the following table.
Activities of elbasvir and grazoprevir in GT1a, GT1b and GT4 reference sequences and clinical isolates in replicon cells:
| Elbasvir | Grazoprevir | |
|---|---|---|
| Reference | EC50 nM | |
| GT1a (H77) | 0.004 | 0.4 |
| GT1b (con 1) | 0.003 | 0.5 |
| GT4 (ED43) | 0.0003 | 0.3 |
| Clinical Isolates | Median EC50 (range) nM | |
| GT1a | 0.005 (0.003-0.009)a | 0.8 (0.4-5.1)d |
| GT1b | 0.009 (0.005-0.01)b | 0.3 (0.2-5.9)e |
| GT4 | 0.0007 (0.0002-34)c | 0.2 (0.11-0.33)a |
Number of isolates tested: a=5, b=4, c=14, d=10, e=9
HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b and 4.
For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions Q30D/E/H/R, L31M/V and Y93C/H/N reduced elbasvir antiviral activity by 6- to 2,000-fold. In genotype 1b replicons, single NS5A substitutions L31F and Y93H reduced elbasvir antiviral activity by 17-fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold. In general, in HCV genotype 1a, 1b or 4 combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity.
For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions D168A/E/G/S/V reduced grazoprevir antiviral activity by 2- to 81-fold. In genotype 1b replicons, single NS3 substitutions F43S, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 3- to 375-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity.
Elbasvir is active in vitro against genotype 1a NS5A substitutions, M28V and Q30L, genotype 1b substitutions, L28M/V, R30Q, L31V, Y93C, and genotype 4 substitution, M31V, which confer resistance to other NS5A inhibitors. In general, other NS5A substitutions conferring resistance to NS5A inhibitors may also confer resistance to elbasvir. NS5A substitutions conferring resistance to elbasvir may reduce the antiviral activity ofother NS5A inhibitors.
Grazoprevir is active in vitro against the following genotype 1a NS3 substitutions which confer resistance to other NS3/4A protease inhibitors: V36A/L/M, Q41R, F43L, T54A/S, V55A/I, Y56F, Q80K/R, V107I, S122A/G/R/T, I132V, R155K, A156S, D168N/S, I170T/V. Grazoprevir is active in vitro against the following genotype 1b NS3 substitutions conferring resistance to other NS3/4A protease inhibitors: V36A/I/L/M, Q41L/R, F43S, T54A/C/G/S, V55A/I, Y56F, Q80L/R, V107I, S122A/G/R, R155E/K/N/Q/S, A156G/S, D168E/N/S, V170A/I/T. Some NS3 substitutions at A156 and at D168 confer reduced antiviral activity to grazoprevir as well as to other NS3/4A protease inhibitors.
The substitutions associated with resistance to NS5B inhibitors do not affect the activity of elbasvir or grazoprevir.
Following administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir peak plasma concentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak plasma concentrations occur at a median Tmax of 2 hours (range of 30 minutes to 3 hours). For elbasvir, the absolute bioavailability is estimated to be 32%. For grazoprevir, the absolute bioavailability after a 200 mg single dose ranged from 15-27% and after multiple 200 mg doses ranged from 20-40%.
Relative to fasting conditions, the administration of a single dose of elbasvir/grazoprevir with a highfat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, elbasvir/grazoprevir may be taken without regard to food.
Elbasvir pharmacokinetics are similar in healthy subjects and HCV-infected subjects. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects.
Based on the population pharmacokinetic modeling in non-cirrhotic, HCV-infected subjects, the geometric mean steady-state elbasvir AUC0-24 and Cmax at 50 mg were 2,180 nM•hr and 137 nM, respectively, and the geometric mean steady-state grazoprevir AUC0-24 and Cmax at 100 mg were 1,860 nM•hr and 220 nM, respectively. Following once daily administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days.
Elbasvir and grazoprevir are extensively bound (>99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
The geometric mean apparent terminal half-life (% geometric mean coefficient of variation) is approximately 24 (24%) hours at 50 mg elbasvir and approximately 31 (34%) hours at 100 mg grazoprevir in HCV-infected subjects.
Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.
The primary route of elimination of elbasvir and grazoprevir is through faeces with almost all (>90%) of the radiolabeled dose recovered in faeces compared to <1% in urine.
Elbasvir pharmacokinetics were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.
In non-HCV-infected subjects with severe renal impairment (eGFR <30 mL/min/1.73 m²) who were not on dialysis, elbasvir and grazoprevir AUC values were increased by 86% and 65%, respectively, compared to non-HCV-infected subjects with normal renal function (eGFR >80 mL/min/1.73 m²). In non-HCV-infected subjects with dialysis-dependent, severe renal impairment, elbasvir and grazoprevir AUC values were unchanged compared to subjects with normal renal function. Concentrations of elbasvir were not quantifiable in the dialysate samples. Less than 0.5% of grazoprevir was recovered in dialysate over a 4-hour dialysis session.
In population pharmacokinetic analysis in HCV-infected patients, elbasvir and grazoprevir AUCs were 25% and 10% higher, respectively, in dialysis-dependent patients and 46% and 40% higher, respectively, in non-dialysis-dependent patients with severe renal impairment compared to elbasvir and grazoprevir AUC in patients without severe renal impairment.
In non-HCV-infected subjects with mild hepatic impairment (Child-Pugh A [CP-A], score of 5-6), elbasvir AUC0-inf was decreased by 40% and grazoprevir steady-state AUC0-24 was increased 70% compared to matched healthy subjects.
In non-HCV-infected subjects with moderate hepatic impairment (Child-Pugh B [CP-B], score of 7-9), and severe hepatic impairment (Child-Pugh C [CP-C], score of 10-15) elbasvir AUC decreased by 28% and 12%, respectively, while the grazoprevir steady-state AUC0-24 was increased 5-fold and 12-fold respectively, compared to matched healthy subjects.
Population PK analyses of HCV-infected patients in Phase 2 and 3 studies demonstrated that grazoprevir steady-state AUC0-24 increased by approximately 65% in HCV-infected patients with compensated cirrhosis (all with CP-A) compared to HCV-infected non-cirrhotic patients, while elbasvir steady-state AUC was similar.
The pharmacokinetics of elbasvir and grazoprevir have been evaluated in 22 paediatric subjects 12 years of age and older who received a daily dose of 50 mg elbasvir/100 mg grazoprevir. Elbasvir and grazoprevir exposures in paediatric subjects were comparable to those observed in adults.
In paediatric subjects 12 years of age and older, the geometric mean steady-state elbasvir AUC0-24 and Cmax at 50 mg were 2,410 nM•hr and 190 nM, respectively, and the geometric mean steady-state grazoprevir AUC0-24 and Cmax at 100 mg were 1,450 nM•hr and 246 nM, respectively.
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects ≥65 years of age compared to subjects less than 65 years of age. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on age.
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on sex.
In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53 kg subject compared to a 77 kg subject. This change is not clinically relevant for grazoprevir. Therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on weight/BMI.
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Whites. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Whites and Black/African Americans. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on race/ethnicity.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction and development with grazoprevir or elbasvir. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Carcinogenicity studies for grazoprevir and elbasvir have not been conducted.
Elbasvir was given to rats and rabbits without eliciting adverse effects on embryofetal or post natal development at up to the highest doses tested (approximately 9- and 17-fold above human exposure in rats and rabbits, respectively). Elbasvir has been shown to cross the placenta in rats and rabbits. Elbasvir was excreted into the milk of lactating rats with concentrations 4-fold that of the maternal plasma concentrations.
Grazoprevir was given to rats and rabbits without eliciting adverse effects on embryofetal or post natal development at up to highest doses tested (approximately 79- and 39-fold above human exposure in rats and rabbits, respectively). Grazoprevir has been shown to cross the placenta in rats and rabbits. Grazoprevir was excreted into the milk of lactating rats with concentrations <1-fold of the maternal plasma concentrations.
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